Osteoarthritis of weight bearing joints of lower limbs in former élite male athletes.

OBJECTIVE--To compare the cumulative 21 year incidence of admission to hospital for osteoarthritis of the hip, knee, and ankle in former élite athletes and control subjects. DESIGN--National population based study. SETTING--Finland. SUBJECTS--2049 male athletes who had represented Finland in international events during 1920-65 and 1403 controls who had been classified healthy at the age of 20. MAIN OUTCOME MEASURES--Hospital admissions for osteoarthritis of the hip, knee, and ankle joints identified from the national hospital discharge registry between 1970 and 1990. RESULTS--Athletes doing endurance sports, mixed sports, and power sports all had higher incidences of admission to hospital for osteoarthritis than controls. Age adjusted odds ratios compared with controls were 1.73 (95% confidence interval 0.99 to 3.01, P = 0.063) in endurance, 1.90 (1.24 to 2.92, P = 0.003) in mixed sports athletes, and 2.17 (1.41 to 3.32, P = 0.0003) in power sports athletes. The mean age at first admission to hospital was higher in endurance athletes (70.6) than in other groups (58.2 in mixed sports, 61.9 in power sports, and 61.2 in controls). Among the 2046 respondents to a questionnaire in 1985, the odds ratios for admission to hospital were similar in all three groups after adjusting for age, occupation, and body mass index at 20 (2.37, 2.42, 2.68). CONCLUSIONS--Athletes from all types of competitive sports are at slightly increased risk of requiring hospital care because of osteoarthritis of the hip, knee, or ankle. Mixed sports and power sports lead to increased admissions for premature osteoarthritis, but in endurance athletes the admissions are at an older age.     

Effects of palmitoylation of replicase protein nsP1 on alphavirus infection

The membrane-associated alphavirus RNA replication complex contains four virus-encoded subunits, the nonstructural proteins nsP1 to nsP4. Semliki Forest virus (SFV) nsP1 is hydrophobically modified by palmitoylation of cysteines 418 to 420. Here we show that Sindbis virus nsP1 is also palmitoylated on the same site (cysteine 420). When mutations preventing nsP1 palmitoylation were introduced into the genomes of these two alphaviruses, the mutant viruses remained viable and replicated to high titers, although their growth was slightly delayed. The subcellular distribution of palmitoylation-defective nsP1 was altered in the mutant: it no longer localized to filopodial extensions, and a fraction of it was soluble. The ultrastructure of the alphavirus replication sites appeared normal, and the localization of the other nonstructural proteins was unaltered in the mutants. In both wild-type- and mutant-virus-infected cells, SFV nsP3 and nsP4 could be extracted from membranes only by alkaline solutions whereas the nsP2-membrane association was looser. Thus, the membrane binding properties of the alphavirus RNA replication complex were not determined by the palmitoylation of nsP1. The nsP1 palmitoylation-defective alphaviruses produced normal plaques in several cell types, but failed to give rise to plaques in HeLa cells, although they induced normal apoptosis of these cells. The SFV mutant was apathogenic in mice: it caused blood viremia, but no infectious virus was detected in the brain.     

Bone and cartilage characteristics in postmenopausal women with mild knee radiographic osteoarthritis and those without radiographic osteoarthritis

Objectives:

To evaluate the association between radiographically-assessed knee osteoarthritis and femoral neck bone characteristics in women with mild knee radiographic osteoarthritis and those without radiographic osteoarthritis.

Methods:

Ninety postmenopausal women (mean age [SD], 58 [4] years; height, 163 [6] cm; weight, 71 [11] kg) participated in this cross-sectional study. The severity of radiographic knee osteoarthritis was defined using Kellgren-Lawrence grades 0=normal (n=12), 1=doubtful (n=25) or 2=minimal (n=53). Femoral neck bone mineral content (BMC), section modulus (Z), and cross-sectional area (CSA) were measured with DXA. The biochemical composition of ipsilateral knee cartilage was estimated using quantitative MRI measures, T2 mapping and dGEMRIC. The associations between radiographic knee osteoarthritis grades and bone and cartilage characteristics were analyzed using generalized linear models.

Results:

Age-, height-, and weight-adjusted femoral neck BMC (p for linearity=0.019), Z (p for linearity=0.033), and CSA (p for linearity=0.019) increased significantly with higher knee osteoarthritis grades. There was no linear relationship between osteoarthritis grades and knee cartilage indices.

Conclusions:

Increased DXA assessed hip bone strength is related to knee osteoarthritis severity. These results are hypothesis driven that there is an inverse relationship between osteoarthritis and osteoporosis. However, MRI assessed measures of cartilage do not discriminate mild radiographic osteoarthritis severity.     

CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling

Altering the number of surface receptors can rapidly modulate cellular responses to extracellular signals. Some receptors, like the transferrin receptor (TfR), are constitutively internalized and recycled to the plasma membrane. Other receptors, like the epidermal growth factor receptor (EGFR), are internalized after ligand binding and then ultimately degraded in the lysosome. Routing internalized receptors to different destinations suggests that distinct molecular mechanisms may direct their movement. Here, we report that the endosome-associated protein hrs is a subunit of a protein complex containing actinin-4, BERP, and myosin V that is necessary for efficient TfR recycling but not for EGFR degradation. The hrs/actinin-4/BERP/myosin V (CART [cytoskeleton-associated recycling or transport]) complex assembles in a linear manner and interrupting binding of any member to its neighbor produces an inhibition of transferrin recycling rate. Disrupting the CART complex results in shunting receptors to a slower recycling pathway that involves the recycling endosome. The novel CART complex may provide a molecular mechanism for the actin-dependence of rapid recycling of constitutively recycled plasma membrane receptors.     

Sunday Driver links axonal transport to damage signaling

Neurons transmit long-range biochemical signals between cell bodies and distant axonal sites or termini. To test the hypothesis that signaling molecules are hitchhikers on axonal vesicles, we focused on the c-Jun NH2-terminal kinase (JNK) scaffolding protein Sunday Driver (syd), which has been proposed to link the molecular motor protein kinesin-1 to axonal vesicles. We found that syd and JNK3 are present on vesicular structures in axons, are transported in both the anterograde and retrograde axonal transport pathways, and interact with kinesin-I and the dynactin complex. Nerve injury induces local activation of JNK, primarily within axons, and activated JNK and syd are then transported primarily retrogradely. In axons, syd and activated JNK colocalize with p150Glued, a subunit of the dynactin complex, and with dynein. Finally, we found that injury induces an enhanced interaction between syd and dynactin. Thus, a mobile axonal JNK-syd complex may generate a transport-dependent axonal damage surveillance system.     

Dog experts' brains distinguish socially relevant body postures similarly in dogs and humans

We read conspecifics' social cues effortlessly, but little is known about our abilities to understand social gestures of other species. To investigate the neural underpinnings of such skills, we used functional magnetic resonance imaging to study the brain activity of experts and non-experts of dog behavior while they observed humans or dogs either interacting with, or facing away from a conspecific. The posterior superior temporal sulcus (pSTS) of both subject groups dissociated humans facing toward each other from humans facing away, and in dog experts, a distinction also occurred for dogs facing toward vs. away in a bilateral area extending from the pSTS to the inferior temporo-occipital cortex: the dissociation of dog behavior was significantly stronger in expert than control group. Furthermore, the control group had stronger pSTS responses to humans than dogs facing toward a conspecific, whereas in dog experts, the responses were of similar magnitude. These findings suggest that dog experts' brains distinguish socially relevant body postures similarly in dogs and humans.     

Predictors of Weight Change in Middle‐aged and Old Men

Objective: Studies on weight change and mortality have yielded inconclusive results. This 10‐year prospective study was undertaken to improve understanding of factors affecting weight change. Research Methods and Procedures: The subjects were 1143 men, aged 36 to 88 years (mean, 53.3 years) at entry. A questionnaire was filled in at entry and at the end of the follow‐up with queries on weight, height, weight at the age of 20, physician‐diagnosed diseases, smoking, alcohol use, dietary habits, leisure physical activity, occupation, present occupational activity, living conditions (living alone or cohabiting), and former athletic status. Further information on morbidity was obtained from selected national registers. Factors predicting weight change during the study were identified by stepwise linear multiple regression analysis. Results: The mean 10‐year weight change was 0.8 (range, ?29 to +24) kg. Age at entry (β‐coefficient, ?0.17, SE 0.02), weight at entry (β, ?0.03, SE 0.01), diabetes at entry (β, ?3.55, SE 1.02), diabetes diagnosed after entry (β, ?3.94, SE 0.96), malignant cancer (β, ?1.60, SE 0.70), being a smoker (β, ?1.59, SE 0.48), and increased physical activity (β, ?1.27, SE 0.54) were significantly (p < 0.05) associated with weight loss in the final model. The model explained 13% of the variance of weight change. Discussion: The results emphasize the complexity of weight change. Some factors associated with weight change are apparently negatively, and some positively, associated with health. This could explain the equivocal findings on weight change and mortality in the literature.     

Relationship between local perfusion and FFA uptake in human skeletal muscle-no effect of increased physical activity and aerobic fitness.

We investigated heredity-independent effects of increased physical activity and aerobic fitness on skeletal muscle free fatty acid (FFA) uptake, perfusion, and their heterogeneity at rest and during exercise. Also, the relationship between local skeletal muscle FFA uptake and perfusion was studied. Nine young adult male monozygotic twin pairs with significant difference in physical activity [229 min (SD 156) average time spent for conditioning exercise per week in more and 98 min (SD 71) in less active twins, P = 0.013] and aerobic fitness [18% (SD 10) difference in maximum O2 uptake] between brothers were studied using positron emission tomography. Submaximal knee-extension exercise increased perfusion, FFA uptake, and oxygen uptake in quadriceps femoris muscles 6-10 times compared with resting values (P < 0.001). More active twins tended to utilize more oxygen, while no differences were found in muscle perfusion or FFA uptake between groups. Mean perfusion and FFA uptake correlated strongly at a whole muscle level, both at rest (r = 0.97, P = 0.03 in more and r = 0.98, P = 0.02 in less active twins) and during exercise (r = 0.99, P = 0.01 and r = 0.94, P = 0.06), but at the voxel level (87 mm3) correlation was only moderate during exercise [r = 0.73 (SD 0.08) vs. r = 0.74 (SD 0.10), P = 0.92] and weak at rest [r = 0.28 (SD 0.13) vs. r = 0.33 (SD 0.21), P = 0.58]. Exercise decreased both perfusion and FFA uptake heterogeneity within the muscles (P < 0.001) similarly in both groups. In conclusion, long-term history of moderately increased physical activity tends to enhance muscle oxidative metabolism, but it does not have any significant influence on the FFA uptake or perfusion rates or their heterogeneity in skeletal muscle. Submaximal knee-extension exercise decreases heterogeneity of muscle FFA uptake and perfusion and improves matching between local muscle perfusion and FFA uptake. Thus it seems that the genetic influence is more important to determine the heterogeneity of perfusion and FFA uptake in skeletal muscle than exercise training.     

Alphavirus Replicase Protein NSP1 Induces Filopodia and Rearrangement of Actin Filaments

Expression of the NSP1 protein of Semliki Forest virus and Sindbis virus in cultured cells induced filopodia-like extensions containing NSP1 but not F actin. The actin stress fibers disappeared, whereas vimentin, keratin, and tubulin networks remained intact. The effects of NSP1 were dependent on its palmitoylation but not on its enzymatic activities and were also observed in virus-infected cells.